A Novel Method for a Stereoselective Synthesis of Trisubstituted Olefin Using Tricarbonyliron Complex: A Highly Stereoselective Synthesis of (all-E)- and (9Z)-Retinoic Acids

Article abstract of DOI:10.1021/jo961041+

In order to establish the stereoselective synthesis of retinoic acids, which are ligand molecules of the retinoic acid receptors (RARs, all-E-isomer) and the retinoid X receptors (RXRs, 9Z-isomer), the reaction of β-ionone-tricarbonyliron complex 7 with carbanions was investigated. Treatment of 7 with the lithium salt of acetonitrile afforded (7E,9E)-β-ionylideneacetonitrile-tricarbonyliron complex 8 exclusively, via addition, dehydration, and migration of tricarbonyliron complex. On the contrary, the reaction of 7 with the lithium enolate of ethyl acetate and subsequent dehydration by thionyl chloride afforded the ethyl (7E,9Z)-β-ionylideneacetate-tricarbonyliron complex 16b predominantly. These compounds (8 and 16b) were converted to the corresponding β-ionylidene-acetaldehyde-tricarbonyliron complexes (10 and 22) in excellent yields, respectively. The Emmons-Horner reaction of these compounds with C5-phosphonate followed by the sequence of decomplexation and alkaline hydrolysis gave the corresponding retinoic acids (26 and 29).

Full text of DOI:10.1021/jo961041+

J . Org. Chem. 1997, 62, 4343-4348
4343
A Novel Meth od for a Ster eoselective Syn th esis of Tr isu bstitu ted
Olefin Usin g Tr ica r bon ylir on Com p lex: A High ly Ster eoselective
Syn th esis of (a ll-E)- a n d (9Z)-Retin oic Acid s†
Akimori Wada,‡ Saeko Hiraishi,‡ Norio Takamura,§ Tadamasa Date,§ Keiichi Aoe,§ and
Masayoshi Ito*,‡
Kobe Pharmaceutical University, 4-19-1, Motoyamakita-machi, Higashinada-ku, Kobe 658, J apan, and
Tanabe Seiyaku Co., Ltd., 3-16-89, Kashima, Yodogawa-ku, Osaka 532, J apan
Received J une 3, 1996X
In order to establish the stereoselective synthesis of retinoic acids, which are ligand molecules of
the retinoic acid receptors (RARs, all-E-isomer) and the retinoid X receptors (RXRs, 9Z-isomer),
the reaction of â-ionone-tricarbonyliron complex 7 with carbanions was investigated. Treatment
of 7 with the lithium salt of acetonitrile afforded (7E,9E)-â-ionylideneacetonitrile-tricarbonyliron
complex 8 exclusively, via addition, dehydration, and migration of tricarbonyliron complex. On
the contrary, the reaction of 7 with the lithium enolate of ethyl acetate and subsequent dehydration
by thionyl chloride afforded the ethyl (7E,9Z)-â-ionylideneacetate-tricarbonyliron complex 16b
predominantly. These compounds (8 and 16b) were converted to the corresponding â-ionylidene-
acetaldehyde-tricarbonyliron complexes (10 and 22) in excellent yields, respectively. The Emmons-
Horner reaction of these compounds with C5-phosphonate followed by the sequence of decomplex-
ation and alkaline hydrolysis gave the corresponding retinoic acids (26 and 29).
Retinoids 1 are covalently or noncovalently bound to
proteins and play an important role as retinoid proteins
in vital cells. The most characteristic feature of these
compounds is that the biological activities depend upon
the stereochemistry of retinoid in the protein. For
example, the chromophore of the visual pigment rhodop-
sin is (11Z)-retinal1 and those of bacteriorhodopsin and
retinochrome, which function as a light-driven proton
pump and for regeneration of rodopsin, are (13Z)- and
(all-E)-retinals, respectively.2 In addition, it has been
recently established that retinoic acids play fundamental
roles in cell differentiation and proliferation through
modulation of their intracellular retinoid receptors.
These receptors comprise two distinct classes, the retinoic
acid receptors (RARs) and the retinoid X receptors
(RXRs), which have (all-E)- and (9Z)-retinoic acids as
ligand molecules, respectively.3
In contrast to the recognition of the significance of the
configuration of retinoids, little is known about the
stereoselective synthesis of geometrical isomers of ret-
inoids. Therefore, high-performance liquid chromatog-
raphy (HPLC) is a powerful tool to obtain pure stereo-
isomers from an isomeric mixture of retinoids. However,
it is not suitable for large-scale preparation. In this
report, we describe the full account of a previous com-
munication4 on the stereoselective synthesis of (7E,9E)-
and (7E,9Z)-â-ionylideneacetaldehydes5 (2a and 2b) us-
ing a tricarbonyliron complex and its application to the
synthesis of retinoic acids.
Resu lts a n d Discu ssion
The conversion of carbonyl compounds to R,â-unsatur-
ated aldehydes is an important reaction in organic
synthesis. For this conversion there are a number of
methods such as Aldol condensation,6 Wittig reaction,7
Peterson olefination,8 Emmons-Horner reaction,9 etc.
However, there are few methods that can be applied to
the stereoselective synthesis of retinoid and related
compounds. Especially, the stereoselective synthesis of
trisubstituted olefins is the most difficult unsolved
problem in this field. Thus, â-ionylideneacetaldehyde 2
possessing a trisubstituted olefin is a very important
material for the synthesis of retinoids and carotenoids,10
† Retinoids and Related Compounds. 21. For part 20, see: Wada,
A.; Sakai, M.; Imamoto, Y.; Shichida, Y.; Yamauchi, M.; Ito, M. J .
Chem. Soc., Perkin Trans. 1. In press.
‡ Kobe Pharmaceutical University.
§ Tanabe Seiyaku Co., Ltd.
X Abstract published in Advance ACS Abstracts, May 15, 1997.
(1) Recent review: Rando, R. R. Angew. Chem., Int. Ed. Engl. 1990,
24, 461.
(5) For structural comparisons standard retinoid numbering has
been used.
(6) (a) Nielsen, A. T.; Houlihan, W. J . Org. React. 1968, 16, 1. (b)
Wittig, G.; Reiff, H. Angew. Chem. 1968, 80, 8; Angew. Chem., Int.
Ed. Engl. 1968, 7, 7.
(7) (a) For reviews, see: Maercker, A. Org. React. 1965, 14, 270. (b)
Trippett, S. Q. Rev. 1963, 17, 406.
(8) (a) Peterson, D. J . J . Org. Chem. 1968, 33, 780. (b) For reviews,
see: Ager, D. J . Synthesis 1984, 384. (c) Ager, D. J . Org. React. 1990,
28, 1.
(2) (a) Ozaki, K.; Terakita, A.; Hara, R.; Hara, T. Vision Res. 1987,
27, 1057. (b) Hara, R.; Hara, T.; Ozaki, K.; Terakita, A.; Eguchi, G.;
Kodama, R.; Takeuchi, T. Retinal Proteins; VNU Science Press:
Utrecht, 1987. (c) Terakita, A.; Hara, R.; Hara, T. Vision Res. 1989,
29, 639.
(3) Heyman, R. A.; Mangelsdorf, D. J .; Dyck, J . A.; Stein, R. B.;
Eichele, G.; Evans, R. M.; Thaller, C. Cell 1992, 68, 397 and references
cited therein.
(9) (a) Horner, L. Chem. Ber. 1958, 83, 733. (b) Wadworth, W. S.;
Emmons, W. D. J . Am. Chem. Soc. 1961, 83, 1733.
(10) Isler, O. Carotenoids; Birkha¨ser Verlag: Basel, 1971.
(4) Wada, A.; Hiraishi, S.; Ito, M. Chem. Pharm. Bull. 1994, 42,
757.
S0022-3263(96)01041-9 CCC: $14.00 © 1997 American Chemical Society

4344 J . Org. Chem., Vol. 62, No. 13, 1997
Wada et al.
Sch em e 1
Sch em e 2
and although there have been a number of reports
dealing with the synthesis of 2,11 no stereoselective
syntheses of 2 has been reported.
In these circumstances, we investigated the possibility
of utilizing diene-tricarbonyliron complexes for the
synthesis of biologically interesting polyolefins. These
complexes have found numerous applications in organic
synthesis due to their ease of preparation, resolution, and
diastereoselective reactivity.12 If the stereocontrolled
formation of a double bond is possible by dehydration of
the adduct 4, easily obtained from the reaction of the
dienyl methyl ketone-tricarbonyliron complex 3 with
nucleophiles, as shown in Scheme 1, it would provide a
new method for the stereoselective synthesis of trisub-
stituted olefins 5 and 6. These compounds have the
partial structures of (9E)- and (9Z)-ionylideneacetalde-
hydes 2a ,b and would be transformed to the correspond-
ing polyolefinic compounds such as retinoic acids. We
employed â-ionone-tricarbonyliron complex 7 as the
starting material for this study.
Sch em e 3
Although â-ionone-tricarbonyliron complex 7 is a
known compound,13 we obtained 7 more efficiently from
â-ionone by replacement of the metalating reagent from
pentacarbonyliron(0) (20%) to dodecacarbonyltriiron(0)14
(98%). Treatment of 7 with the lithium salt of acetoni-
trile in THF at -70 °C afforded 8 in 91% yield via
addition, dehydration, and successive migration of tri-
carbonyliron (Scheme 2). A similar migration of tricar-
bonyliron has been already reported by Salzer et al. in
the reaction of sorbaldehyde-tricarbonyliron with car-
banions.15 The geometry of the double bond at the 9
position of 8 was determined as E compared to the
corresponding â-ionylideneacetonitrile 916 after oxidative
decomplexation using copper(II) chloride in ethanol.17 The
transformation of 8 to the corresponding aldehyde 10 was
achieved quantitatively by DIBALH reduction. Decom-
plexation of 10 by copper(II) chloride in ethanol gave a
complex mixture, and the desired product 2a was not
obtained. When decomplexation of 10 was carried out
by using iron(III) chloride,17 isomerization occurred to
provide an isomeric mixture of double bonds at the 9
position. Therefore, the uncomplexed 7E,9E-aldehyde 2a
was prepared from 9 by DIBALH reduction in quantita-
tive yield without isomerization of the double bond.
Next, we focused our attention on the stereoselective
synthesis of 7E,9Z-aldehyde 2b. Recently, Gre¨e and co-
workers developed a convenient method for the isomer-
ization of E,E-dienals to E,Z-dienals via an iron penta-
dienyl cation complex obtained from the corresponding
dienol.18 In order to apply this methodology to the
synthesis of 2b, the aldehyde-tricarbonyliron complex
10 was converted to the E,E-dienol 11 in excellent yield
by NaBH4 reduction (Scheme 3). Treatment of 11 with
triphenylcarbenium tetrafluoroborate gave the dehy-
drated product 13 in 77% yield. None of the desired Z,E-
dienol 14 was detected. The formation of 13 is easily
understandable from consideration of the pentadienyl
cation intermediate 12, which is immediately deproto-
nated from the methylene group at the 4 position to
afford 13. The stereochemistry of 13 at the 6 and 8
positions was determined to be that shown in Scheme 3
by 2D NOESY experiments. Thus, the presence of
corresponding crosspeaks confirms the proximity of H-7
(δ 5.71) to Me-5 (δ 1.83) and the proximityt of H-8 (δ 2.22)
to Me-1 (δ 1.18 and 1.30) and H-11 (δ 0.40).
(11) (a) Dugger, R. W.; Heathcock, C. H. Synth. Commun. 1980, 10,
509. (b) Robeson, C. D.; Cawley, J . D.; Weisler, L.; Stern, M. H.;
Eddinger, C. C.; Chechak, A. J . J . Am. Chem. Soc. 1955, 77, 4111. (c)
Ishikawa, Y. Bull. Chem. Soc. J pn. 1963, 36, 1527. (d) Ko¨brich, von
G.; Breckoff, W. E.; Drischel, W. Liebigs Ann. Chem. 1967, 704, 51. (e)
Arens, J . F.; van Dorp, D. A. Recl. Trav. Chim. Pays-Bas 1948, 67,
973. (f) Pardoen, J . A.; Mulder, P. P. J .; van den Berg, E. M. M.;
Lugtenburg, J . Can. J . Chem. 1985, 63, 1431.
Subsequently, we studied the reaction of 7 with
another nucleophile (Scheme 4). The reaction of 7 with
the lithium enolate of ethyl acetate in THF at -70 °C
gave the adduct 15 as a single product in 89% yield. In
comparison with the reaction of acetonitrile, in this case
dehydration and subsequent migration of the tricarbo-
nyliron complex was not observed. We suppose that the
(12) Gre¨e, R. Synthesis 1989, 341.
(13) Cais, M.; Maoz, N. J . Organomet. Chem. 1966, 5, 370.
(14) MacFarlane, W.; Wilkinson, G. Inorg. Synth. 1966, 8, 181.
(15) Hafner, A.; von Philpsborn, W.; Saltzer, A. Angew. Chem., Int.
Ed. Engl. 1985, 24, 126.
(16) Ramamurthy, V.; Tustin, G.; Yau, C. C.; Liu, R. S. H. Tetra-
hedron 1975, 31, 193.
(17) Pearson, A. J .; Lai, Y. S.; Lu, W.; Pinkerton, A. A. J . Org. Chem.
1989, 54, 3882.
(18) Morey, J .; Gre¨e, D.; Mosset, P.; Toupet, L.; Gre¨e, R. Tetrahedron
Lett. 1987, 28, 2959.

Stereoselective Synthesis of (all-E)- and (9Z)-Retinoic Acids
J . Org. Chem., Vol. 62, No. 13, 1997 4345
Sch em e 4
Sch em e 5
Sch em e 6
electron-withdrawing effect of the ester is less than that
of the nitrile, so dehydration does not occur under the
reaction conditions from the reaction intermediate. The
structure of 15 was confirmed by single-crystal X-ray
analysis.19 Furthermore, this structure was consistent
with the deduction from the reaction mechanism that the
carbonyl group of 7 has the s-cis conformation and the
nucleophile attacks the other side of the tricarbonyliron
complex.20 Dehydration of 15 by thionyl chloride afforded
the 9Z-ester 16b predominantly (65%) accompanied by
its 9E-isomer 16a (10%). The stereochemistry of the
newly produced double bond of these compounds was
determined by their transformation to the corresponding
â-ionylidene esters11b (17 and its isomer) after oxidative
decomplexation. In contrast, treatment of 15 with p-
TsOH under reflux in benzene afforded the 9Z-ester 16b
(31%) and the nonconjugated ester 1813 (43%). It is
noteworthy that 16b was isomerized to 18 under the
reaction conditions, and this fact indicates that ester 18
seems to be the thermodynamically more stable product.
The formation of 18 was rationalized from consideration
of the transoid pentadienyl cation intermediate21 19,
which was immediately deprotonated from the five meth-
yl group in the same manner as 13 to provide 18. This
reaction mechanism predicts that the stereochemistry of
18 at the 6 and 8 positions are Z and E, respectively,
because elimination of the hydroxyl group occurs from
the back side of the tricarbonyliron complex and spon-
tanious deprotonation gives the product 18. This specu-
lation is in accordance with the confirmed structure
determined by 2D NOESY experiments. Thus, the
presence of corresponding crosspeaks confirms the prox-
imity of H-7 (δ 3.14) to Me-1 (δ 1.20 and 1.24) and Me-9
(δ 1.75) and the proximity of H-8 (δ 5.02) to CH2-9 (δ 2.83
and 2.88).
Z-olefin 16b was obtained as the major product. The
high stereoselectivity of this dehydration can be under-
stood by a chelation mechanism between the iron and
the ester group in the reaction intermediate as shown in
the Newman projections (Scheme 5). In the favored
transition state [B], the tricarbonyliron group plays an
important role in regulating the formation of the double
bond. There are two possible routes for the formation of
the Z-olefin through the transition state [B]: (i) syn-
elimination via a six-membered cyclic intermediate as in
the pyrolysis of esters, thioesters, and carbamates23
(route A) or (ii) anti-elimination through a carbonium
cation intermediate derived from the E1 mechanism
(route B). Although we could not obtain definite evi-
dence, route B seems most likely for the formation of the
Z-olefin because of the fact that dehydration by p-TsOH,
in which reaction route A is impossible, gave the Z-olefin
16b in 31% yield. A similar chelation mechanism
between iron and a carbonyl group has already been
reported in the hydroxylation of a phenoxo ferric complex
to a catecholate complex with m-chloroperoxybenzoic
acid.24 In addition, the significance of chelation between
the iron and the ester is supported by the results that in
the dehydration of the adduct prepared from the reaction
of 7 with a nucleophile not having a heteroatom such as
ethylmagnesium bromide or vinylmagnesium bromide,
only a complex mixture was produced and the Z-olefin
was not isolated at all.
Our first attempt at transformation of 16b to the
aldehyde 2b by DIBALH reduction and subsequent MnO2
oxidation of the alcohol 20 following decomplexation was
unsuccessful because isomerization of the double bond
gave the 7E,9E-aldehyde 2a (Scheme 6). It seems that
the aldehyde is not a suitable functional group in the
decomplexation step; the reason is not clear yet. There-
It is well-known that dehydration with thionyl chloride
proceeds via an E1 mechanism to afford the most stable
product.22 However, in the case of 15, the unstable
(19) The authors have deposited atomic coordinates for this struc-
ture with the Cambridge Crystallographic Data Center. The coordi-
nates can be obtained, on request, from the Director, Cambridge
Crystallographic Center, 12 Union Road, Cambridge, CB2 1EZ, U.K.
(20) Clinton, N. A.; Lillya, C. P. J . Am. Chem. Soc. 1970, 92, 3058.
(21) Roush, W. R.; Wada, C. K. Tetrahedron Lett. 1994, 35, 7347.
(22) Lomas, J . S.; Sagatys, D. S.; Dubois, J . E. Tetrahedron Lett.
1971, 599.
(23) (a) Depuy, C. H.; King, R. W. Chem. Rev. 1960, 431. (b) Nace,
H. R. Org. React. 1962, 12, 57. (c) de Groot, A.; Evenhuis, B.; Wynberg,
H. J . Org. Chem. 1968, 33, 2214. (d) Paquette, L. A.; Trpva, M. P.
Tetrahedron Lett. 1987, 28, 2795. (e) Newman, M. S.; Hetzel, F. W. J .
Org. Chem. 1969, 34, 3604. (f) Berti, G. J . Am. Chem. Soc. 1954, 76,
1213. (g) Gerlach, H.; Mu¨ler, W. Helv. Chim. Acta 1972, 55, 2277.
(24) Kitajima, N.; Ito, M.; Fukai, H.; Moro-oka, Y. J . Am. Chem.
Soc. 1993, 115, 9335.

4346 J . Org. Chem., Vol. 62, No. 13, 1997
Wada et al.
300, or 500 MHz. Analytical HPLC was carried out with a
column, LiChrosorb Si-60 (5 µm), 0.4 × 30 cm, and preparative
HPLC with a LiChrosorb Si-60 (5 µm), 1.0 × 30 cm. Column
chromatography (CC) under reduced pressure by aspirator (ca.
30 mmHg) was performed by using Merck silica gel 60. All
reactions were carried out under a nitrogen atmosphere.
Materials were obtained from commercial supplies and used
without further purification except when otherwise noted. THF
and ether were purified by distillation from benzophenone-
sodium ketyl under nitrogen. Diisopropylamine was purified
by distillation from CaH2. Standard workup means that the
organic layers were finally washed with brine, dried over
anhydrous sodium sulfate (Na2SO4), filtered, and concentrated
in vacuo below 30 °C using a rotary evaporator.
Sch em e 7
Tr ica r bon yl[(η4-3,4,1,2)-(3E)-4-(2,6,6-tr im eth yl-1-cyclo-
h exen -1-yl)-3-bu ten -2-on e]ir on (0) (7). A mixture of â-ion-
one (2.85 g, 15 mmol) and dodecacarbonyltriiron14 (9 g, 29
mmol) in benzene (40 mL) was heated under reflux for 20 h.
The resulting mixture was passed through out the short
aluminum column to remove the excess reagent, and eluent
was concentrated under reduced pressure. The residue was
purified by CC (ether:hexane 1:6) to give the tricarbonyliron
complex 713 (4.9 g, 98%) as orange solids: UV-vis 252.5 nm
(sh); IR 2050, 1980 and 1960 (Fe(CO)3), 1670 (ketone) cm-1
;
1H NMR (300 MHz) δ 1.22 (s, 3H), 1.41 (s, 3H), 1.45 (s, 3H),
1.5-1.7 (m, 4H), 1.8-2.1 (m, 2H), 2.17 (s, 3H), 2.40 (d, J ) 9
Hz, 1H), 5.66 (d, J ) 9 Hz, 1H); 13C NMR (75 MHz) δ 19.6,
24.1, 29.7, 29.9, 34.1, 35.3, 38.7, 42.4, 51.6, 70.3, 81.5, 117.2,
204.6 (4C).
fore, after decomplexation of 16b, the ester 17 was
converted to the aldehyde 2b by LiAlH4 reduction and
subsequent MnO2 oxidation. It is the first time that a
stereoselective synthesis of 2b has been achieved using
a tricarbonyliron complex (Scheme 6). Alternatively,
alcohol 20 was converted to the aldehyde 22 in good yield
without decomplexation by mild oxidation using Mu-
kaiyama’s method.25
Finally, the aldehydes 10 and 22 were converted to the
corresponding retinoic acids (Scheme 7). The Emmons-
Horner reaction of 10 with the C5-phosphonate 23 was
carried out using n-BuLi to give the ester 24a and its
13Z isomer 24b . The stereochemistry (E-form) of the
11,12 double bond in 24a ,b was determined on the basis
of the coupling constants of the 11-H signal in the NMR
spectrum. It is noteworthy that although the C5-phos-
phonate 23 was used as a mixture of double bonds [ca.
4:1] in the condensation, the ratio of the all-E-isomer in
the products increased dramatically [all-E:13Z ) ca. 12:
1]. A similar result has been reported by Gedye and co-
workers.26 After decomplexation of 24, the final trans-
formation of 25 to the corresponding acid 2627 was
achieved by hydrolysis using sodium hydroxide at 50 °C
in 98% yield. In the same manner, the aldehyde 22 was
converted to the corresponding (9Z)-retinoic acid 2928 in
good yield.
Tr ica r b on yl[(η4-2,3,4,5)-(2E,4E)-3-m et h yl-5-(2,6,6-t r i-
m et h yl-1-cycloh exen -1-yl)-2,4-p en t a d ien en it r ile]ir on -
(0) (8). To a stirred solution of LDA, prepared from n-BuLi
(1.6 M hexane solution, 5.7 mL, 9.1 mmol) and diisopropyl-
amine (1.3 ml, 9.1 mmol) in THF (30 mL), was added a solution
of acetonitrile (0.52 mL, 9.1 mmol) in THF (6 mL) at -70 °C,
and the resulting mixture was stirred for an additional 30 min.
A solution of the tricarbonyliron complex 7 (1.0 g, 3.01 mmol)
in THF (10 mL) was added at -70 °C, and the mixture was
allowed to come to -50 °C. After addition of saturated
aqueous NH4Cl (40 mL) and evaporation of the solvent, the
organics were extracted with ether followed by standard
workup. The residue was purified by CC (ether:hexane 1:4)
to give the nitrile 8 (967 mg, 91%) as orange prisms: mp 110-
113 °C (ether-hexane); UV-vis 327, 243 nm; IR 2200 (nitrile),
1
2050 and 2000 (Fe(CO)3) cm-1; H NMR (200 MHz) δ 0.48 (s,
1H), 1.13 (s, 3H), 1.24 (s, 3H), 1.4-1.6 (m, 4H), 1.83 (s, 3H),
1.95 (d, J ) 11 Hz, 1H), 2.02 (br t, J ) 6 Hz, 2H), 2.51 (s, 3H),
5.89 (d, J ) 11 Hz, 1H); 13C NMR (75 MHz) δ 18.7, 21.0, 23.1,
25.4, 28.9, 29.6, 34.8, 35.2, 42.1, 65.1, 87.6, 95.9, 120.8, 134.4,
137.3, 209.6 (3C); HRMS calcd for C18H21FeNO3 355.0872,
found 355.0866 (M+).
(2E,4E)-3-Meth yl-5-(2,6,6-tr im eth yl-1-cycloh exen -1-yl)-
2,4-p en ta d ien en itr ile (9). To a stirred solution of nitrile 8
(350 mg, 0.99 mmol) in ethanol (20 mL) was added a solution
of copper(II) chloride (570 mg, 4.2 mmol) in ethanol (10 mL)
at rt, and the resulting mixture was stirred for an additional
30 min. After removal of ethanol, the residue was extracted
with ether followed by standard workup. The residue was
purified by CC (ether:hexane 3:7) to give the decomplexed
nitrile 916 (202 mg, 95%) as a pale yellow oil: UV-vis 304,
In summary, we have developed a stereoselective
synthesis of 2 which, for the first time, includes a
Z-trisubstituted olefin in the polyene chain. This method
will provide a novel route for the preparation of (all-E)-
or (9Z)-vitamin A and related compounds.
252 nm; IR 2200 (nitrile), 1680 and 1605 (double bond) cm-1
;
1H NMR (200 MHz) δ 1.02 (s, 6H), 1.4-1.7 (m, 6H), 1.70 (s,
3H), 2.04 (br t, 2H), 2.20 (s, 3H), 5.16 (s, 1H), 6.14 (d, J ) 16.5
Hz, 1H), 6.59 (d, J ) 16.5 Hz, 1H).
Exp er im en ta l Section
Tr ica r b on yl[(η4-2,3,4,5)-(2E,4E)-3-m et h yl-5-(2,6,6-t r i-
m et h yl-1-cycloh exen -1-yl)-2,4-p en t a d ien a l]ir on (0) (10).
To a solution of nitrile 8 (300 mg, 0.85 mmol) in dry CH2Cl2
(15 mL) was added dropwise DIBALH (0.20 mL, 1.10 mmol)
in dry CH2Cl2 (2 mL) at 0 °C. After the solution was stirred
for an additional 30 min at 0 °C, the excess DIBALH was
destroyed by addition of moist silica gel (H2O:SiO2 1:5). After
filtration with Celite, the filtrate was dried over Na2SO4. The
solvent was evaporated off, and the residue was purified by
CC (ether:hexane 1:4) to afford the aldehyde 10 (204 mg,
quantitative) as orange prisms: mp 78.5-80 °C (ether-
hexane); UV-vis 261 (sh) nm; IR 2049 and 1980 (Fe(CO)3),
Melting points are uncorrected. UV-vis spectra were
recorded in ethanol, IR spectra in chloroform, and 1H NMR
spectra in deuteriochloroform unless otherwise stated at 200,
(25) Saigo, K.; Morikawa, A.; Mukaiyama, T. Bull. Chem. Soc. J pn.
1976, 49, 1656.
(26) Gedye, R. N.; Westaway, K. C.; Arora, P.; Bisson, R.; Khalil, A.
H. Can. J . Chem. 1977, 55, 1218.
(27) Tanaka, H.; Kagechika, H.; Kawachi, E.; Fukasawa, H.; Hash-
imoto, Y.; Syudo, K. J . Med. Chem. 1992, 35, 567.
(28) Boehm, M. F.; McClurg, M. R.; Pathirana, C.; Mangelsdorf, D.;
White, S. K.; Hebert, J .; Winn, D.; Goldman, M. E.; Heymann, R. A.
J . Med. Chem. 1994, 37, 408.

Stereoselective Synthesis of (all-E)- and (9Z)-Retinoic Acids
J . Org. Chem., Vol. 62, No. 13, 1997 4347
1680 (aldehyde), 1650 (double bond) cm-1; 1H NMR (200 MHz)
δ 1.08 (d, J ) 6.5 Hz, 1H), 1.08 and 1.27 (each s, each 3H),
1.4-1.6 (m, 4H), 1.84 (s, 3H), 2.04 (br t, J ) 7 Hz, 2H), 2.42
(d, J ) 11 Hz, 1H), 2.58 (s, 3H), 5.89 (d, J ) 11 Hz, 1H), 9.49
(d, J ) 6.5 Hz, 1H); 13C NMR (75 MHz) δ 19.3, 20.5, 23.7, 29.4,
30.3, 35.5, 35.8, 42.6, 56.9, 66.2, 89.3, 98.6, 135.2, 137.7, 195.8,
210.8 (3C); HRMS calcd for C18H21FeO4 358.0868, found
358.0868 (M+).
followed by standard workup. The residue was purified by
CC (ether:hexane 1:9) to give the esters 16a (20 mg, 10%) and
16b (124 mg, 65%) as pale orange solids, respectively.
16a : UV-vis 280 (sh) nm; IR 2050 and 1980 (Fe(CO)3), 1688
1
(ester), 1603 (double bond) cm-1; H NMR (200 MHz) δ 1.28
(s, 3H), 1.30 (t, J ) 7 Hz, 3H), 1.43 and 1.49 (each s, each 3H),
1.5-1.8 (m, 4H), 1.8-2.0 (m, 2H), 2.27 (s, 3H), 2.67 (d, J ) 9
Hz, 1H), 4.18 (q, J ) 7 Hz, 2H), 5.38 (d, J ) 9 Hz, 1H), 5.79 (s,
1H); 13C NMR (75 MHz) δ 14.4, 18.3, 19.6, 23.7, 29.7, 34.2,
35.2, 38.9, 42.6, 58.6, 59.6, 68.4, 79.3, 113.3, 114.6, 159.0, 166.7,
CO disappeared; HRMS calcd for C20H26FeO5 402.1131, found
402.1121(M+).
(2E,4E)-3-Meth yl-5-(2,6,6-tr im eth yl-1-cycloh exen -1-yl)-
2,4-p en ta d ien a l (2a ). In the same manner as described for
the preparation of 10 from 8, the nitrile 9 (185 mg, 0.86 mmol)
was converted to the corresponding aldehyde 2a (188 mg,
1
quant.). The IR and H NMR spectra are consistent with those
16b: UV-vis 285 (sh) nm; IR 2050 and 1970 (Fe(CO)3), 1690
of literature.11a
1
(ester), 1605 (double bond) cm-1; H NMR (200 MHz) δ 1.29
(t, J ) 7 Hz, 3H) 1.36 (s, 3H), 1.41 and 1.46 (each s, each 3H),
1.5-1.7 (m, 4H), 1.82 (s, 3H) 1.8-2.0 (m, 2H), 4.20 (q, J ) 7
Hz, 2H), 4.74 (d, J ) 9.5 Hz, 1H), 5.38 (d, J ) 9.5 Hz, 1H),
5.68 (s, 1H); 13C NMR (75 MHz) δ 14.4, 19.6, 20.4, 23.5, 29.6,
34.3, 35.2, 42.7, 53.7, 59.6, 69.2, 82.0, 114.1, 115.7, 158.0, 166.3,
211.3 (3C); HRMS calcd for C20H26FeO5 (M+) 402.1131, found
402.1129.
Tr ica r b on yl[(η4-2,3,4,5)-(2E,4E)-3-m et h yl-5-(2,6,6-t r i-
m et h yl-1-cycloh exen -1-yl)-2,4-p en t a d ien ol]ir on (0) (11).
To a stirred solution of the aldehyde 10 (700 mg, 2.0 mmol) in
ethanol (7 mL) was added NaBH4 (148 mg, 3.9 mmol) portion-
wise at 0 °C, and the mixture was stirred for an additional 30
min. The reaction mixture was poured into ice-water (15 mL),
and the organics were extracted with ether followed by
standard workup. The residue was purified by CC (ether:
hexane 3:7) to provide the alcohol-iron complex 11 (543 mg,
76%) as a pale yellow oil: UV-vis 317.5 (sh), 205 nm; IR 3613
and 3500-3200 (hydroxy), 2050, 1980 and 1960 (Fe(CO)3)
Eth yl (2Z,4E)-3-Meth yl-5-(2,6,6-tr im eth yl-1-cycloh exen -
1-yl)-2,4-p en ta d ien oa te (17). To a stirred solution of the
ester complex 16b (1.28 g, 3.18 mmol) in ethanol (50 mL) was
added a solution of copper(II) chloride (2.14 g, 15.9 mmol) in
ethanol (20 mL) at rt, and the resulting mixture was stirred
for an additional 30 min. After removal of ethanol, the resi-
due was extracted with ether followed by standard workup.
The residue was purified by CC (ether:hexane 1:7) to give
the decomplexed ester 17 (808 mg, 97%) as a pale yellow oil.
The IR and 1H NMR spectra are consistent with those of
literature.11b
1
cm-1; H NMR (300 MHz) δ 1.01 (br t, J ) 6.5 Hz, 1H), 1.14
and 1.24 (each s, each 3H), 1.3-1.6 (m, 4H), 1.79 (s, 3H), 1.82
(d, J ) 11 Hz, 1H), 1.9-2.1 (m, 2H), 2.30 (s, 3H), 3.81 (dd, J
) 2, 8 Hz, 1H), 3.90 (dd, J ) 12, 6 Hz, 1H), 5.70 (d, J ) 11 Hz,
1H); HRMS calcd for C18H22FeO3 342.0919, found 342.0922 (M+
- H2O).
Tr ica r b on yl[(η4-1,2,3,4)-(3Z,5Z)-3-m et h yl-5-(2,6,6-t r i-
m eth yl-2-cycloh exen yliden e)-1,3-pen tadien e]ir on (0) (13).
To a stirred solution of the alcohol complex 11 (211 mg, 0.59
mmol) in CH2Cl2 (10 mL) was added a solution of triphenyl-
carbenium tetrafluoroborate (193 mg, 0.59 mmol) in CH2Cl2
(3 mL) at 0 °C, and the resulting mixture was stirred for an
additional 15 min. After addition of water (15 ml), the mixture
was stirred for 30 min and the organics were extracted with
CH2Cl2 followed by standard workup. The residue was puri-
fied by CC (ether:hexane 5:95) to give the triene complex 13
(153 mg, 77%) as a pale yellow oil: UV-vis 324 (sh), 281 nm;
Tr ica r bon yl[eth yl (η4-5,1,2,1)-(3E,5Z)-3-m eth yl-5-((6,6-
dim eth yl-2-m eth yliden e)cycloh exyliden e)-3-pen ten oate]-
ir on (0) (18). A mixture of the ester complex 15 (664 mg, 1.58
mmol) and p-TsOH (25 mg) in benzene (30 mL) was heated
under reflux for 0.5 h. After cooling, water (40 mL) was added
and then the organics were extracted with benzene followed
by standard workup. The residue was purified by CC (ether:
hexane 1:7) to afford the esters 16b (197 mg, 31%) and 1813
(271 mg, 43%) as pale yellow oils, respectively.
18: UV-vis 240 nm (sh); IR 2050, 1975 and 1960 sh (Fe-
1
IR 2050, 1980 and 1960 (Fe(CO)3) cm-1; H NMR (200 MHz)
1
(CO)3), 1720 (ester) cm-1; H NMR (200 MHz) δ 1.20 (3H, s,
δ 0.40 (dd, J ) 9, 3 Hz, 1H), 1.18 and 1.30 (each s, each 3H),
1.49 (t, J ) 6.5 Hz, 2H), 1.70 (dd, J ) 7, 3 Hz, 1H), 1.83 (br s,
3H), 2.0-2.1 (m, 2H), 2.22 (d, J ) 12 Hz, 1H), 2.27 (s, 3H),
5.18 (br t, J ) 8 Hz, 1H), 5.71 (d, J ) 12 Hz, 1H), 5.73 (br t,
J ) 4.5 Hz, 1H); 13C NMR (75 MHz) δ 20.7, 23.2, 24.6, 29.3,
30.7, 36.5, 37.7, 41.7, 65.5, 84.3, 101.4, 125.6, 129.1, 135.6,
145.5, 213.6 (3C); HRMS calcd for C18H22FeO3 342.0919, found
342.0910 (M+).
3H) 1.23 (t, J ) 7 Hz, 3H) 1.24 (s, 3H), 1.6-1.7 (m, 2H), 1.69
(d, J ) 2 Hz, 1H), 1.72 (d, J ) 2 Hz, 1H), 1.75 (s, 3H), 1.8-1.9
(m, 2H), 2.08 (dt, J ) 16.5, 5 Hz, 1H), 2.75 (1H, ddd, J ) 16.5,
8, 6 Hz, 1H), 2.83 (d J ) 14.5 Hz, 1H), 2.88 (1H, d, J ) 14.5
Hz, 1H), 3.14 (d, J ) 8.5 Hz, 1H), 4.10 (q, J ) 7 Hz, 2H), 5.02
(d, J ) 8.5 Hz, 1H); 13C NMR (75 MHz) δ 14.2, 17.3, 18.9, 30.5,
32.9, 33.3, 33.9, 37.6, 39.3, 44.9, 45.4, 60.5, 107.0, 113.3, 129.8,
130.6, 171.4, 211.0 (3C); HRMS calcd for C20H26FeO5 (M+)
402.1131, found 402.1120 (M+).
Tr ica r bon yl[eth yl (η4-4,5,1,2)-(4E)-(3R*,4R*,2S*)-3-h y-
d r oxy-3-m et h yl-5-(2,6,6-t r im et h yl-1-cycloh exen -1-yl)-4-
p en ten oa te]ir on (0) (15). In the same manner as described
for the preparation of 8, the tricarbonyliron complex 7 (1.0 g,
3.1 mmol) was reacted with ethyl acetate (0.61 mL, 6.2 mmol).
The residue was purified by CC (ether:hexane 1:4) to give the
adduct complex 15 (1.16 g, 89%) as pale yellow prisms: mp
85-86 °C (CH2Cl2-hexane); UV-vis 237 nm (sh); IR 3500
(hydroxy), 2050, 1980 and 1960 (Fe(CO)3) cm-1; 1H NMR (200
MHz) δ 1.07 (s, 3H), 1.28 (t, J ) 7 Hz, 3H) 1.37 and 1.40 (each
s, each 3H), 1.42 (s, 3H), 1.4-1.6 (m, 4H), 1.7-2.0 (m, 2H),
2.12 (d, J ) 9 Hz, 1H), 2.63 (s, 2H), 3.67 (s, 1H), 4.21 (q, J )
7 Hz, 2H), 5.17 (d, J ) 9 Hz, 1H); 13C NMR (75 MHz) δ 14.2,
19.6, 23.4, 30.0, 30.9, 34.2, 34.9, 39.1, 42.6, 48.8, 60.9, 67.0,
69.1, 71.4, 79.6, 112.3, 172.4, 210.5 (3C); HRMS calcd for
C20H27FeO5 403.1207, found 403.1220 (M+ - OH).
(2Z,4E)-3-Meth yl-5-(2,6,6-tr im eth yl-1-cycloh exen -1-yl)-
2,4-p en ta d ien a l (2b). A solution of the ester 17 (83 mg, 0.32
mmol) in ether (4 mL) was added dropwise to a stirred
suspension of LiAlH4 (24 mg, 0.63 mmol) in ether (4 mL) at 0
°C, and the resulting mixture was stirred at 0 °C for 30 min.
The excess LiAlH4 was destroyed by addition of moist ether
and water, and then the organics were extracted with ether
followed by standard workup. To the residue were added
active MnO2 (560 mg, 6.4 mmol) and CH2Cl2 (15 mL), and the
resulting mixture was shaken at rt for 5 h. The mixture was
filtered through Celite, and the filtrate was concentrated in
vacuo to give the crude product, which was purified by CC
(ether:hexane 1:7) to afford the aldehyde 2b (180 mg, 79%) as
1
a yellow oil. The IR and H NMR are consisted with those of
literature.11b
Tr ica r bon yl[eth yl (η4-4,5,1,2)-(2E,4E)-3-m eth yl-5-(2,6,6-
t r im et h yl-1-cycloh exen -1-yl)-2,4-p en t a d ien oa t e]ir on (0)
(16a ) a n d Tr ica r bon yl[eth yl (η4-4,5,1,2)-(2Z,4E)-3-m eth yl-
5-(2,6,6-tr im eth yl-1-cycloh exen -1-yl)-2,4-p en ta d ien oa te]-
ir on (0) (16b). To a solution of the hydroxy ester 15 (200 mg,
0.48 mmol) in pyridine (2 mL) was added thionyl chloride (0.06
mL, 0.96 mmol) at 0 °C, and the resulting mixture was stirred
for 10 min. The reaction was quenched with 5% HCl (10 mL)
in the ice-bath, and the organics were extracted with ether
Tr ica r b on yl[(η4-4,5,1,2)-(2Z,4E)-3-m et h yl-5-(2,6,6-t r i-
m eth yl-1-cycoh exen -1-yl)-2,4-p en ta d ien a l]ir on (0) (22). To
a solution of the ester complex 16b (700 mg, 1.74 mmol) in
dry ether (10 mL) was added dropwise DIBALH (0.7 mL, 4
mmol) in dry ether (3 mL) at -45 °C. After the solution was
stirred at the same temperature for an additional 30 min, the
excess DIBALH was destroyed by addition of moist ether and
water. Cold 15% tartaric acid (4.5 mL, 4.5 mmol) was added,
and the resulting mixture was stirred at rt for 2 h. The

4348 J . Org. Chem., Vol. 62, No. 13, 1997
Wada et al.
organics were extracted with ether followed by standard
workup. To a dissolved solution of this residue in dry THF
(10 mL) was added diisopropylmagnesium bromide (0.68 M
ether solution, 3.3 mL, 2.26 mmol) at 0 °C. After the solution
was stirred for 10 min, a solution of azodicarbonyldipiperidine
(530 mg, 1.24 mmol) in dry THF (4 mL) was added at 0 °C,
and the resulting mixture was stirred for an additional 20 min.
The reaction was quenched with brine (20 mL), and then the
organics were extracted with ether (3 × 30 mL) followed by
standard workup. The residue was purified by CC (ether:
hexane 1:4) to afford the aldehyde complex 22 (445 mg, 71%)
as a yellow oil: UV-vis 301.8 nm; IR 2038, 1978 and 1960 sh
the reaction mixture was made acidic with 5% HCl, and then
the organics were extracted with ethyl acetate followed by
standard workup. The residue was purified by CC (ethyl
acetate:hexane 3:1) to give the retinoic acid 26 (23 mg, 98%)
as yellow solids. The IR and 1H NMR spectra are consistent
with those of literature.27
Tr icar bon yl[eth yl (η4-5,6,7,8)-(9Z)-r etin oate]ir on (0) (27a)
a n d Tr ica r bon yl[et h yl (η4-5,6,7,8)-(9Z,13Z)-r et in oa t e]-
ir on (0) (27b). In the same manner as described for the
preparation of 24, the aldehyde complex 22 (33 mg, 0.09 mmol)
was converted to the corresponding retinoate-tricarbonyliron
complex 27 as a isomeric mixture (54 mg, quant). Pure
samples were obtained by HPLC (ether:benzene:hexane 1:25:
74) separation as pale yellow oils, respectively.
1
(Fe(CO)3), 1655 (aldehyde) cm-1; H NMR (300 MHz) δ 1.33
(3H, s, 3H), 1.42 and 1.47 (each s, each 3H), 1.5-1.7 (m, 4H),
1.8-2.1 (m, 2H), 1.97 (s, 3H), 4.05 (d, J ) 10 Hz, 1H), 5.46 (d,
J ) 10 Hz, 1H), 5.86 (d, J ) 6 Hz, 1H), 10.07 (d, J ) 6 Hz,
1H); 13C NMR (75 MHz) δ 19.3, 23.7, 25.7, 29.5, 30.4, 35.6,
36.1, 42.6, 58.9, 69.0, 95.3, 100.0, 135.8, 137.4, 194.5, 210.5
(3C); HRMS calcd for C18H22FeO4 358.0868, found 358.0868
(M+).
9Z-Isom er 27a : UV-vis 365, 325 (sh), 260 nm; IR 2030,
1967 and 1950 (Fe(CO)3), 1700 (ester), 1593 (double bond)
cm-1 1H NMR (300 MHz) δ 1.29 (s, 3H), 1.29 (t, J ) 7 Hz,
;
3H), 1.42 and 1.47 (each s, each 3H), 1.5-1.7 (m, 4H), 1.87 (s,
3H), 1.9-2.0 (m, 2H), 2.36 (s, 3H), 3.45 (d, J ) 10 Hz, 1H),
4.17 (q, J ) 7 Hz, 2H), 5.25 (d, J ) 10 Hz, 1H), 5.79 (s, 1H),
6.02 (d, J ) 11.5 Hz, 1H), 6.23, (d, J ) 15 Hz, 1H), 7.08 (dd,
J ) 15, 11 Hz, 1H); 13C NMR (75 MHz) δ 13.5, 14.4, 19.6, 20.3,
23.3, 29.7, 34.2, 35.2, 39.0, 42.7, 55.4, 59.7, 67.5, 80.3, 113.6,
119.0, 127.9, 134.6, 142.0, 152.8, 167.2, 212.3 (3C); HRMS calcd
for C25H32FeO5 468.1600, found 468.1581 (M+).
Tr ica r bon yl[eth yl (η4-7,8,9,10)-(a ll-E)-r etin oa te]ir on -
(0) (24a ) a n d Tr ica r bon yl[eth yl (η4-7,8,9,10)-(13Z)-r etin -
oa te]ir on (0) (24b). To a solution of diethyl (3-(methoxycar-
bonyl)-2-methyl-2-propenyl)phosphonate (23)26 (E:Z ) 4:1) (391
mg, 2 mmol) in THF (5.5 mL) was added n-BuLi (1.6 M hexane
solution, 0.99 mL, 1.66 mmol) at 0 °C. After the mixture was
stirred for 30 min, a solution of the aldehyde complex 10 (280
mg, 0.78 mmol) in THF (5 mL) was added. The resulting
mixture was stirred for an additional 5 h. The reaction was
quenched with saturated NH4Cl (5 mL) and extracted with
ether followed by standard workup. The residue was purified
by CC (ether:hexane 1:9) to give the pentaenyl ester 24a (328
mg, 89%) and its isomer 24b (27 mg, 7%) as yellow oils,
respectively.
9Z,13Z-Isom er 27b: UV-vis 360.4, 340 (sh), 261 nm; IR
2029 and 1965 (Fe(CO)3), 1697 (ester), 1594 (double bond)
cm-1 1H NMR (300 MHz) δ 1.27 (s, 3H), 1.29 (t, J ) 7 Hz,
;
3H), 1.42 and 1.46 (each s, each 3H), 1.5-1.7 (m, 4H), 1.87 (s,
3H), 1.8-2.0 (m, 2H), 2.08 (s, 3H), 3.47 (d, J ) 9 Hz, 1H), 4.16
(q, J ) 7 Hz, 2H), 5.25 (d, J ) 9 Hz, 1H), 5.68 (s, 1H), 6.12 (d,
J ) 11.5 Hz, 1H), 7.08 (dd, J ) 15, 11.5Hz, 1H), 7.73 (d, J )
15 Hz, 1H); 13C NMR (75 MHz) δ 14.4, 19.6, 20.3, 20.8, 23.3,
29.7, 34.2, 35.2, 39.0, 42.7, 55.6, 59.6, 67.2, 80.4, 113.3, 116.9,
128.7, 128.8, 130.9, 142.2, 151.3, 166.5, 212.5 (3C); HRMS calcd
for C25H32FeO5 468.1600, found 468.1609 (M+).
a ll-E-Isom er 24a : UV-vis 318.4 nm; IR 2035 and 1972 (Fe-
1
(CO)3), 1700 (ester), 1606 (double bond) cm-1; H NMR (300
MHz) δ 1.15 and 1.27 (each s, each 3H), 1.28 (t, J ) 7 Hz,
3H), 1.4-1.6 (m, 4H), 1.73 (d, J ) 9 Hz, 1H), 1.82 (s, 3H), 2.01
(br t, J ) 7.5 Hz, 2H), 2.05 (d, J ) 11 Hz, 1H), 2.28 (s, 3H),
2.38 (s, 3H), 4.17 (q, J ) 7 Hz, 2H), 5.70 (d, J ) 11 Hz, 1H),
5.77 (s, 1H), 6.31 (d, J ) 15 Hz, 1H), 6.38 (dd, J ) 15, 9 Hz,
1H); 13C NMR (75 MHz) δ 13.8, 14.4, 18.9, 20.1, 23.0, 28.9,
29.8, 34.9, 35.2, 42.2, 59.7, 60.6, 61.7, 85.5, 95.5, 118.5, 133.6,
134.5, 134.9, 135.1, 152.0, 167.2, 212.5 (3C); HRMS calcd for
C25H32FeO5 468.1600, found 468.1592 (M+).
Eth yl (9Z)-Retin oa te (28). In the same manner as
described for the decomplexation of 8, the retinoate complex
27a (15 mg, 0.03 mmol) was converted to the corresponding
1
retinoate 28 (10.3 mg, 98%). The IR and H NMR spectra are
consistent with those of literature.28
(9Z)-Retin oic Acid (29). In the same manner as described
for the preparation of 26, the retinoate 28 (50 mg, 0.15 mmol)
was hydrolyzed to the corresponding retinoic acid 29 (37 mg,
74%) as yellow solids. The IR and 1H NMR spectra are
consistent with those of literature.28
13Z-Isom er 24b: UV-vis 329.2nm; IR 2034 and 1973 (Fe-
1
(CO)3), 1702 (ester), 1610 (double bond) cm-1; H NMR (300
MHz) δ 1.15 and 1.27 (each s, each 3H), 1.28 (t, J ) 7 Hz,
3H), 1.4-1.6 (m, 4H), 1.82 (s, 3H), 1.85 (d, J ) 10.5 Hz, 1H),
2.00 (s, 1H), 2.01 (br t, J ) 7.5 Hz, 2H), 2.08 (d, J ) 10.5 Hz,
1H), 2.37 (s, 3H), 4.16 (q, J ) 7 Hz, 2H), 5.65 (s, 1H), 5.70 (d,
J ) 10.5 Hz, 1H), 6.32 (dd, J ) 15.5, 10.5 Hz, 1H), 7.85 (dd, J
) 15.5 Hz, 1H); 13C NMR (75 MHz) δ 14.3, 18.9, 20.2, 20.9,
23.1, 28.9, 29.9, 34.9, 35.2, 42.2, 59.7, 61.0, 61.9, 85.7, 96.0,
116.3, 127.7, 134.9, 135.1, 136.2, 150.6, 166.5, 212.5 (3C);
HRMS calcd for C25H32FeO5 468.1600, found 468.1600 (M+).
Eth yl (a ll-E)-Retin oa te (25). In the same manner as
described for the decomplexation of 8, the retinoate complex
24a (66 mg, 0.14 mmol) was converted to the corresponding
retinoate 25 (26 mg, 56%). The IR and 1H NMR spectra are
consistent with those of literature.27
Ack n ow led gm en t. This research was supported in
part by a Grant-in-Aid for Scientific Research from
Ministry of Education, Science and Culture (J apan) and
the Science Research Promotion Fund from J apan
Private School Promotion Foundation.
Su p p or t in g In for m a t ion Ava ila b le: 1H NMR and 13C
NMR spectra for compounds 7, 8, 10, 13, 15, 16a ,b, 18, 22,
24a ,b, and 27a ,b, 2D-NOESY spectra for 13 and 18, and an
ORTEP diagram of the X-ray structure of adduct 15 (29 pages).
This material is contained in libraries on microfiche, im-
mediately follows this article in the microfilm version of the
journal, and can be ordered from the ACS; see any current
masthead page for ordering information.
(a ll-E)-Retin oic Acid (26). A mixture of the retinoate 25
(25 mg, 0.78 mmol) and 25% NaOH solution (5 mL) in
methanol (5 mL) was heated at 50 °C for 30 min. After cooling,
J O961041+